There is tremendous need for drugs against Trypanosomatids. The World Health Organization estimates that 16-18 million people in Latin America are chronically infected with T. cruzi, the causative agent of Chagas' disease, over 20 million are infected with Leishmania spp., the causative agents of Leishmania spp., the causative agents of Leishmaniasis, and 300,000 cases of infection with T. brucei, the causative agent of African Sleeping Sickness, as reported annually. Chronic infections often lead to fatality, and currently used drugs are highly toxic and usually ineffective. Protein prenylation (the attachment of 15-carbon farnesyl and 20-carbon geranylgeranyl groups to proteins) is a recently discovered event in eukaryotic cells. We have recently shown that prenylation occurs in Trypanosomatids. We have made significant progress in the purification of the protein farnesyltransferase (the enzyme that attaches farnesyl groups to proteins) from the insect form of T. brucei, and efforts are underway to clone the genes encoding the subunits of this enzyme and to over- express the protein for structural studies. Protein farnesyltransferase inhibitors are being developed by many pharmaceutical companies for the treatment of human malignancies, since it has been shown that the oncogenic Ras proteins require farnesylation to function. We have found that these inhibitors block protein prenylation in T. brucei and cause cell death. A preliminary exploration of the substrate specificity of the T. brucei enzyme shows that it will be possible to prepare parasite-selective inhibitors. This, plus the facts that protein farnesyltransferase inhibitors are not very toxic to mammalian cells and that there is already a tremendous amount of medical chemical studies on these inhibitors, makes the parasite enzyme an ideal drug target.